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Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

DOI: 10.1073/pnas.1814685116 DOI Help

Authors: Beatriz Baragaña (University of Dundee) , Barbara Forte (University of Dundee) , Ryan Choi (University of Washington) , Stephen Nakazawa Hewitt (University of Washington) , Juan A. Bueren-calabuig (University of Dundee) , Joao Pedro Pisco (University of Dundee) , Caroline Peet (University of Dundee) , David M. Dranow (Seattle Structural Genomics Center for Infectious Disease; Beryllium Discovery Corp.) , David A. Robinson (University of Dundee) , Chimed Jansen (University of Dundee) , Neil R. Norcross (University of Dundee) , Sumiti Vinayak (University of Georgia) , Mark Anderson (University of Dundee) , Carrie F. Brooks (University of Georgia) , Caitlin A. Cooper (University of Georgia) , Sebastian Damerow (University of Dundee) , Michael Delves (Imperial College) , Karen Dowers (University of Dundee) , James Duffy (Medicines for Malaria Venture) , Thomas E. Edwards (Seattle Structural Genomics Center for Infectious Disease; Beryllium Discovery Corp.) , Irene Hallyburton (University of Dundee) , Benjamin G. Horst (Seattle Structural Genomics Center for Infectious Disease; University of Washington) , Matthew A. Hulverson (University of Washington) , Liam Ferguson (University of Dundee) , María Belén Jiménez-díaz (The Art of Discovery) , Rajiv S. Jumani (University of Vermont) , Donald D. Lorimer (Seattle Structural Genomics Center for Infectious Disease; Beryllium Discovery Corp.) , Melissa S. Love (Calibr at Scripps Research) , Steven Maher (University of Georgia) , Holly Matthews (Imperial College) , Case W. Mcnamara (Calibr at Scripps Research) , Peter Miller (University of Vermont) , Sandra O’neill (University of Dundee) , Kayode K. Ojo (University of Washington) , Maria Osuna-cabello (University of Dundee) , Erika Pinto (University of Dundee) , John Post (University of Dundee) , Jennifer Riley (University of Dundee) , Matthias Rottmann (Swiss Tropical and Public Health Institute; Universität Basel) , Laura M. Sanz (GlaxoSmithKline) , Paul Scullion (University of Dundee) , Arvind Sharma (International Centre for Genetic Engineering and Biotechnology) , Sharon M. Shepherd (University of Dundee) , Yoko Shishikura (University of Dundee) , Frederick R. C. Simeons (University of Dundee) , Erin E. Stebbins (University of Vermont) , Laste Stojanovski (University of Dundee) , Ursula Straschil (Imperial College) , Fabio K. Tamaki (University of Dundee) , Jevgenia Tamjar (GlaxoSmithKline) , Leah S. Torrie (University of Dundee) , Amélie Vantaux (Institut Pasteur du Cambodge) , Benoît Witkowski (Institut Pasteur du Cambodge) , Sergio Wittlin (Swiss Tropical and Public Health Institute; Universität Basel) , Manickam Yogavel (International Centre for Genetic Engineering and Biotechnology) , Fabio Zuccotto (University of Dundee) , Iñigo Angulo-barturen (The Art of Discovery) , Robert Sinden (Imperial College) , Jake Baum (Imperial College) , Francisco-javier Gamo (GlaxoSmithKline) , Pascal Mäser (Universität Basel) , Dennis E. Kyle (University of Georgia) , Elizabeth A. Winzeler (University of California) , Peter J. Myler (Seattle Structural Genomics Center for Infectious Disease; University of Washington) , Paul G. Wyatt (University of Dundee) , David Floyd (University of Toronto) , David Matthews (University of Toronto) , Amit Sharma (International Centre for Genetic Engineering and Biotechnology) , Boris Striepen (University of Georgia; University of Pennsylvania) , Christopher D. Huston (University of Vermont) , David W. Gray (University of Dundee) , Alan H. Fairlamb (University of Dundee) , Andrei V. Pisliakov (University of Dundee) , Chris Walpole (Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal) , Kevin D. Read (University of Dundee) , Wesley C. Van Voorhis (University of Washington) , Ian H. Gilbert (University of Dundee)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 116 , PAGES 7015 - 7020

State: Published (Approved)
Published: April 2019
Diamond Proposal Number(s): 10071

Open Access Open Access

Abstract: Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

Journal Keywords: malaria; cryptosporidiosist; RNA synthetase

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF

Documents:
7015.full.pdf